Osteoarthritis (OA) is a progressive degenerative disorder accompanied by pain and characterized by a breakdown of cartilage in articular joints, a deterioration of the synovial fluid present in the articular joints, and a resulting osteosclerosis.
Osteoarthritis increases with age, with a probability higher than 60% of those 60 years old or older.
Today, to remediate to the mechanical pain accompanied with OA, the present therapy is generally, either therapeutic with administration of analgesic or anti-inflammatory agents or a surgical therapy with partial or total joint replacement. An alternative approach is viscosupplementation which is an injection into the joint of a biocompatible viscous (e.g. Hyaluronic acid) lubricant that reduces friction and pain.
Viscosupplementation is used to supplement synovial fluid that lubricates and protects the articular joints. Indeed, in OA patient, the synovial fluid is modified with a decrease of concentration and molecular weight (Mw) of hyaluronan (or salt of hyaluronic acid HA).
Intra-articular injections comprising high molecular weight of HA preparations are currently available and used to treat knee, hip, carpometacarpal joint of the thumb or ankle. These preparations require one (Durolane™, Q-Med AB, Uppsala, Sweden), three (Synvisc®, high molecular weight cross-linked HA, Orthovisc®) to five (Hyalgan®, Supartz®) intra-articular (IA) injections (1 to 3 ml containing 5 to 20 mg/ml HA per injection according the joint).
TABLE 1Hyaluronic acid (HA) preparationsAverageTrade nameCorporationMw (kD)SYNVISC ®(Hylan G-20)Biomatrix (Canada)6.000-7.000HEALON ®Pharmacia/Upjohn1.900-3900 (Sweden)ORTHOVISC ®Anika (USA)1.700-2.900ARTHRUM ®LCA (France)2.000ADANT ®Meiji Seika (Japan) 900-1.200SUPARTZ ®, ARTZ ®,Seikagaku (Japan) 600-1.200ARTZAL ®OSTENIL ®Chemedica (France)1.200HYALGAN ®Fidia (Italy)500-730DUROLANE ®Q-Med AB (Sweden)≧9000 
HA preparations vary in a number of characteristics, including for example, the source of HA (animal-derived or bacterial), the concentration and Mw of HA and the type and degree of chemical crosslinking used, if any. Usually, most injectable HA preparations, once injected, have residence half-life between hours to several days.
Several studies have compared the efficacy of the above-mentioned products and differently concluded to a marked reduction of pain and improved function of patients with knee OA. Some concluded that at best there is small effect compared to placebo injection. Others observed that 3-5 weekly injections of one of the above products, significantly improved the pain and functional status of patients with OA and that, although the onset of improvement was delayed by 3-4 weeks, the effect can last at least six months and up after treatment cessation. Other observed beneficial effects on OA symptoms, not only for knee OA but also for ankle or carpometacarpal joint of the thumb OA, but also adverse effects.
Moreover, clinical effect may be rapid at 1 week and may last for six months or more, but in all cases, multiple injections are essential for a prolonged (six month to one year) effect on osteoarthritic pain primarily because of the short residence half-life of most HA preparations.
Endly, WO2007/135114 describes viscosupplementation with polysaccharides compositions of a mixture of alginate and chitosan without generating insoluble coacervates. Coacervates are due to the polycationic nature of chitosan that makes compatibility difficult with other polysaccharides such as hyaluronic acid (a polyanion) or alginate. According to WO2007/135114, precipitation/coarcervation of polysaccharides such as chitosan and alginate prevents any formulation thereof as an injectable composition.
In WO2007/135114 a composition with an aqueous mixture of chitosan of a high degree of derivatization of at least 40% and an alginate is therefore described as highly viscous without generating insoluble coacervates.
A continued need exists to develop new intra-articular supplement product that protect cartilage against mechanical strains, provide effective relief to OA patient without necessitating multiple injections and to avoid adverse effect.
We have now found a new method of producing a homogenous hydrogel matrix comprising alginate and chitosan wherein chitosan is of low molecular weight and coacervates. The resulting alginate/chitosan beads obtainable by the new method remain surprisingly homogenous and stable when used for intra-articularly supplementation.
We have now found a new method and composition for single intra-articular supplementation of chitosan/alginate beads with a long-term residence (at least two weeks) in the joint without increasing viscosity of the synovial fluid.
The foregoing summary and the following description are not restrictive of the invention as claimed.